Electrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection

Patrick Vigneault, Sandrine Parent, Pushpinder Kanda, Connor Michie, Darryl R. Davis () and Stanley Nattel ()
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Patrick Vigneault: Montreal Heart Institute, Université de Montréal
Sandrine Parent: University of Ottawa
Pushpinder Kanda: University of Ottawa
Connor Michie: University of Ottawa
Darryl R. Davis: University of Ottawa
Stanley Nattel: Montreal Heart Institute, Université de Montréal

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract We have shown that calcium-activated potassium (KCa)-channels regulate fundamental progenitor-cell functions, including proliferation, but their contribution to cell-therapy effectiveness is unknown. Here, we test the participation of KCa-channels in human heart explant-derived cell (EDC) physiology and therapeutic potential. TRAM34-sensitive KCa3.1-channels, encoded by the KCNN4 gene, are exclusively expressed in therapeutically bioactive EDC subfractions and maintain a strongly polarized resting potential; whereas therapeutically inert EDCs lack KCa3.1 channels and exhibit depolarized resting potentials. Somatic gene transfer of KCNN4 results in membrane hyperpolarization and increases intracellular [Ca2+], which boosts cell-proliferation and the production of pro-healing cytokines/nanoparticles. Intramyocardial injection of EDCs after KCNN4-gene overexpression markedly increases the salutary effects of EDCs on cardiac function, viable myocardium and peri-infarct neovascularization in a well-established murine model of ischemic cardiomyopathy. Thus, electrophysiological engineering provides a potentially valuable strategy to improve the therapeutic value of progenitor cells for cardioprotection and possibly other indications.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25180-8

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DOI: 10.1038/s41467-021-25180-8

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